Stroke and other brain traumas are the third leading cause of mortality and morbidity. The natural polyamines, putrescine, spermidine and spermine, and ornithine decarboxylase (ODC), the first and rate limiting enzyme of polyamine biosynthesis, were reported to contribute to the damage caused by neurotrauma. The hippocampal slice will be used as a model to study polyamines in two types of neurotrauma: N-methyl-D- aspartate (NMDA) induced excitotoxicity and anoxia. The deterioration and recovery of field potentials recorded in the synaptic and pyramidal layers of area CA1 will be used as a measure of neural damage and neuroprotection. This method has been successfully used by other investigators using different drugs. The inhibition of ODC by alpha-difluoromethylornithine (DFMO), reduces the degree of NMDA induced excitoxicity. However, we have recently shown that DFMO also antagonizes GABAergic transmission counteracting its neuroprotective activity, thus making DFMO a poor choice as a neuroprotective agent. Five ODC inhibitors, never before tested in the CNS, will be assayed for anti GABAergic activity, using paired-pulse inhibition and pharmacologically isolated GABAergic potentials. The neuroprotective activity of these inhibitors will be tested. On the bases of their structures we expect some of the novel ODC inhibitors to have low or none anti GABAergic activity and thus be more neuroprotective than DFMO. The increase in ODC activity that follows trauma causes a large increase in putrescine. Putrescine was reported to increase Ca++ influx and facilitate synaptic release of excitatory amino acids. We plan to test the hypothesis that putrescine is neurotoxic during neurotrauma. Spermine is released from damaged neurons during ischemia and some authors have suggested that it might cause neural damage. However, according to our results spermine could be neuroprotective because it decreases synaptic transmission in slices. We propose to test the hypothesis that spermine is neuroprotective. We plan to test whether polyamine concentrations in brain slices can be modulated by neuroprotective drugs during and after neurotrauma. To do that we will measure the concentration of polyamines in slices and in the washout solution without trauma, during trauma and after trauma in the presence or absence of neuroprotective drugs. The polyamines will be determined by an HPLC method in use in our laboratory. We expect to provide clues about novel neuroprotective drugs and to clarify the role of polyamines in neurotrauma.